Collaborative Research: Engineering an Angiogenic Cardiac Patch

该项目的目标是开发和评估一种能够在缺血性损伤后保持心脏功能的生物相容性植入物。通过促进心脏功能组织的恢复，这种植入物将显著提高心脏病发作后的愈合和恢复。植入物将被制成一种增强的水凝胶（心脏贴片），很容易固定在心脏上，并且能够储存和释放生长因子到受伤的组织中。通过在受伤组织周围生长新的毛细血管网络来响应植入物，将实现功能性组织恢复。目前，美国每年有92万例心脏病发作（心肌梗死）。受伤心脏组织供血不足是限制愈合的关键因素。因此，在受损组织中发展成熟的微血管网络可以为恢复心脏功能提供重大进展。心脏贴片将由一种新型复合生物材料组成，该复合材料由电纺丝纤维组成，通过共价交联分散，巯基透明质酸和肝素基凝胶，形成合成细胞外基质。成熟的微血管网络将通过凝胶中多种生长因子的有序释放以及这些生长因子与透明质酸的协同相互作用来诱导。在本项目中，我们将验证肝素调节的生长因子释放可以显著改善受损心肌的血运重建，诱导功能良好的灌注血管，从而恢复缺血性损伤后的心功能。该复合材料的物理化学性质将在体外进行评估，并根据指定的设计标准对其组合进行优化。通过测量植入后心脏样本的微血管增殖和成熟度，将预先加载选定生长因子的贴片缝合到缺血心脏上，从而量化其血管生成能力。随着时间的推移，诱导血管的功能将通过活体动物的非侵入性磁共振成像来确定。这种成像也将有助于确定心脏功能的改善情况。通过支持患病心脏组织的功能恢复，这种植入物将显著减轻缺血性心脏损伤带来的痛苦负担。拟议的研究将建立基于丝和透明质酸的水凝胶的设计和制造方案，通过持续的生长因子输送诱导新的毛细血管进入病变组织，从而恢复病变心脏组织的功能。通过开发一种优越的基质，我们的研究结果可以在适当的时候显著影响心脏病的治疗。此外，正如提案文本所述，pi在教育、培训和指导学生方面有着悠久的历史。拟议的项目将允许我们继续吸引本科生和研究生参与我们正在进行的研究工作，扩大研究培训，教育经验和为参与的学生提供的机会。作为招收学生参加该项目过程的一部分，将充分注意我国各机构为招收和留住妇女和研究中代表性不足的少数民族而建立的基础设施。其中包括新英格兰高等教育卓越委员会多元化项目，这是一个招募代表性不足的少数族裔学生参加项目并传播有关机会信息的主要论坛，以及塔夫茨大学医学院的少数族裔外展项目。在过去的十年里，这些项目非常成功地吸引了代表性不足的本科生在塔夫茨大学度过暑假，参与生物医学科学研究。

0932456/0933470Peattie/FirpoIntellectual meritThe goal of the proposed project is to develop and evaluate a biocompatible implant capable of preserving cardiac function following ischemic injury. By facilitating restoration of functional heart tissue, this implant will significantly improve healing and recovery after heart attack. The implant will be fabricated as a reinforced hydrogel (the cardiac patch), easily securable to the heart and capable of storing and releasing growth factors into the injured tissue. Functional tissue restoration will be achieved through the growth of a new capillary network surrounding the injured tissue in response to the implant. Currently, 920,000 heart attacks (myocardial infarction) occur annually in the US. Inadequate blood supply to the injured heart tissue is a critical limitation to healing. Development of mature microvessel networks in the damaged tissue can therefore provide a major advance towards restoring heart function. The cardiac patch will consist of a novel composite biomaterial composed of electrospun silk fibers dispersed through a covalently crosslinked, thiol-modified hyaluronic acid and heparin-based gel, creating a synthetic extracellular matrix. Mature microvessel networks will be induced by controlled, sequential release of multiple growth factors from the gel and by synergistic interactions of those growth factors with hyaluronic acid. In the proposed project, we will test the hypothesis that heparin-regulated growth factor release can dramatically improve the revascularization of damaged myocardium, eliciting functional, perfused vessels that restore cardiac function after ischemic injury. Physico-chemical properties of the composite will be evaluated in vitro and its composition optimized with regard to specified design criteria. The angiogenic capacity of patches pre-loaded with selected growth factors then sutured onto ischemic hearts will be quantified by measurement of microvessel proliferation and maturity in heart samples post-implantation. The functionality of elicited vessels will then be determined by non-invasive magnetic resonance imaging in live animals over time. Such imaging will also allow determination of improvements in heart function.Broader impactBy supporting restoration of functionality to diseased heart tissue, this implant will significantly reduce the burden of suffering associated with ischemic heart damage. The proposed investigations will establish protocols for design and fabrication of silk and hyaluronic acid-based hydrogels that restore functional cardiac tissue in diseased heart tissue by eliciting the growth of new capillary blood vessels into diseased tissue through sustained growth factor delivery. By developing a superior matrix, our results can in due course significantly impact therapeutic treatment of heart disease.Furthermore, as is described in the proposal text, the PIs have a long history of significant commitment to education, training and mentorship of students. The proposed project will permit us to continue to engage undergraduate as well as graduate students in our ongoing research efforts, expanding the research training, educational experience and opportunities available to the students involved. As part of the process of recruitment of students into the project, full attention will be given to the infrastructure in place in our institutions for recruiting and retaining women and underrepresented minorities in research. These include the New England Board of Higher Education Excellence through Diversity Program, a major forum for recruitment of underrepresented minority students for programs and for disseminating information about the opportunities, and the Tufts University School of Medicine minority outreach program. For the last ten years, these programs have been highly successful in attracting underrepresented undergraduate students to spend summers at Tufts involved in biomedical science research.